Ectoin and ectoin derivatives as moisturizers in cosmetics

ABSTRACT

Cosmetic preparations for the care of aged, dry or irritated skin are prepared using a compound of the formula Ia or Ib

DESCRIPTION

[0001] Ectoin and ectoin derivatives as moisturizers in cosmetics.

[0002] It is known that(S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid (ectoin) isfound in extremely halophilic microorganisms and that it plays a role inthe osmoregulation of these organisms (E. A. Galinski et al., Eur. J.Biochem., 149 (1985) pages 135-139).

[0003] A major task of cosmetics is the preservation or restoration ofthe normal state of the skin. In addition to other criteria, stabilizingthe moisture content of the skin plays an important role. Under normalconditions, the skin itself is capable of regulating its moisturecontent. A change in the external environment, such as, for example, acold dry atmosphere, very rapidly results in the state in which the skinsurface is dried out. The surface of the skin turns flaky and tends tochap slightly. The skin is highly sensitive to chemical and physicalfactors. In patients suffering from atopy, these skin symptoms areobserved irrespectively of the age, while, in healthy humans, the dryskin condition becomes more pronounced as they grow older (B. Idson,Cosmetics & Toiletries, 107 (1992), pages 69-78). This skin conditioncan be prevented as well as counteracted by using suitable moisturizingpreparations.

[0004] The ingredients used for this purpose in moisturizingpreparations differ with regard to two, different principles of action.The occlusive substances (for example paraffin oils) form a barrier onthe skin surface which is impermeable to water vapor, whereby theyprevent trans-epidermal water loss (TEWL) of the skin. In contrast,intradermal substances such as glycerol bind the water in the skin.

[0005] It has now been found that cosmetic preparations comprising atleast one compound of the formula Ia or Ib improve and stabilize thehydration of the human skin.

[0006] The invention relates to the use of at least one compound of theformula Ia or Ib

[0007] and/or a physiologically acceptable salt of the compound of theformula Ia or Ib and/or a stereoisomeric form of the compound of theformula Ia or Ib for the preparation of cosmetic products; R¹ beingdefined as follows:

[0008] a) a hydrogen atom or

[0009] b) (C₁-C₄)-alkyl,

[0010] R² being defined as follows:

[0011] a) a hydrogen atom,

[0012] b) —COOH,

[0013] c)

[0014] d)

[0015] in which R⁵ is

[0016] 1) a hydrogen atom,

[0017] 2) (C₁-C₄)-alkyl,

[0018] 3) an amino acid radical,

[0019] 4) a dipeptide radical or

[0020] 5) a tripeptide radical,

[0021] R³ and R⁴ independently of one another being defined as follows:

[0022] a) a hydrogen atom or

[0023] b) —OH, and

[0024] n is the number 1, 2 or 3.

[0025] The compounds of the formula Ia or Ib can be present in thecosmetic products in the form of the optical isomers, diastereomers,racemates, zwitterions, cations or in the form of a mixture of these.

[0026] Preferred is the use of at least one compound of the formula Iaor Ib, R₁ being defined as follows:

[0027] a) a hydrogen atom or

[0028] b) methyl,

[0029] R² being defined as follows:

[0030] a) a hydrogen atom or

[0031] b) —COOH,

[0032] R³ and R⁴ independently of one another being defined as follows:

[0033] a) a hydrogen atom or

[0034] b) —OH, and

[0035] n is the number 2.

[0036] The invention furthermore relates to cosmetic products comprising(S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid and/or(S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid.

[0037] The invention furthermore relates to processes for thepreparation of the compound of the formula Ia or Ib which comprise

[0038] A) reacting a compound of the formula II

[0039] in which R¹ is as in formula Ia,

[0040] with a compound of the formula III

[0041] in the presence of an alcohol to give a compound of the formulaIa or Ib,

[0042] R³, R⁴ and n being defined as in formula Ia and R² being ahydrogen atom or —COOH, or

[0043] B) reacting a compound of the formula Ia or Ib in which R² is—COOH with an alkyl halide to give the corresponding carboxylic estersof the compound of the formula Ia or Ib, or

[0044] C) reacting a compound of the formula Ia or Ib in which R² is anactivated carboxylic ester with an amine of the formula NH₂—R⁵ to givethe corresponding carboxamide of the compound of the formula Ia or Ib.

[0045] The term “amino acid” is to be understood as meaning thestereoisomeric forms, for example the D and L forms of The followingcompounds:

[0046] sparagine, arginine, aspartic acid, glutamine, glutamic acid,β-alanine, γ-aminobutyrate, Nε-acetyllysine, Nδ-acetylornithine,Nγ-acetyldiaminobutyrate, Nα-acetyldiaminobutyrate, histidine,isoleucine, leucine, methionine, phenylalanine, serine, threonine andtyrosine. L-amino acids are preferred. Amino acid radicals are derivedfrom the corresponding amino acids.

[0047] The following amino acid radicals are preferred:

[0048] Gly, Ala, Ser, Thr, Val, β-Ala, γ-aminobutyrate, Asp, Glu, Asn,Gln, Nε-acetyllysine, Nδ-acetylornithine, Nγ-acetyldiaminobutyrate,Nα-acetyldiaminobutyrate.

[0049] The amino acids are abbreviated as is generally customary. Thedi- or tripeptide radicals are acid amides by their chemical nature anddisintegrate into two or three amino acids upon hydrolysis. The aminoacids in the di- or tripeptide radical are linked to each other by amidelinkage.

[0050] Examples of suitably physiologically acceptable salts of thecompound of the formula Ia or Ib are, for example, alkali metal salts,alkaline earth metal salts or ammonium salts, such as the sodium salt,potassium salt, magnesium salt, calcium salt, triethylamine salt ortris(2-hydroxy-ethyl)amine salt. Other physiologically acceptable saltsof the compound of the formula Ia or Ib result from reaction withinorganic acids such as hydrochloric acid, sulfuric acid and phosphoricacid or with organic carboxylic or sulfonic acids such as acetic acid,citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid andp-toluenesulfonic acid. Compounds of the formula Ia or Ib in which thesame number of basic and acidic groups, such as carboxyl or aminogroups, exist, form internal salts.

[0051] The invention furthermore relates to a process for thepreparation of di- or tripeptides or the salts thereof, which comprises

[0052] a) reacting a segment with a C-terminal free carboxylic group oran activated derivative thereof with a suitable segment with anN-terminal free amino group, or

[0053] b) synthesizing the di- or tripeptide stepwise, and,

[0054] if appropriate, eliminating one or more protective groups in thecompound obtained by a) or b) which have been introduced temporarily forprotecting other functions and, if appropriate, converting the resultingcompounds to a physiologically acceptable salt thereof.

[0055] The di- or tripeptides are prepared stepwise starting from theC-terminal end or by coupling segments, following the general methods ofpeptide chemistry (Houben-Weyl, Methoden der Organischen Chemie [Methodsin Organic Chemistry], Volume 15/1,2). The peptide coupling steps can beeffected for example by the mixed anhydride method, by active radicalsor azides or by the carbodiimide method, in particular with the additionof substances which accelerate the reaction and prevent racemisization,such as 1-hydroxybenzotriazole, N-hydroxysuccinimide,3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine,N-hydroxy-5-norbornene-2,3-dicarboximide, furthermore using activederivatives of 1-hydroxybenzotriazole or anhydrides of phosphoric acids,phosphonic acids and phosphinic acids, at a reaction temperature of −10°C. to the boiling point of the solvent, preferably from −5° C. to 40° C.

[0056] Suitable solvents are dimethylformamide, dimethylacetamide,N-methylpyrrolidone or dimethyl sulfoxide. Solvents such as methylenechloride, chloroform or tetrahydrofuran may also be employed if thereactants are sufficiently soluble.

[0057] If it is required to prevent secondary reactions or if requiredfor the synthesis of specific peptides, the functional groups in theside chain of amino acids are additionally protected by suitableprotecting groups, the following being employed in the main: Arg(Tos),Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzl), Asp(OBut), Cys(4-MeBzl),Cys(Asm), Cys(SBut), Glu(Obzl), Glu(Obut), His(Tos), His(Fmoc),His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc) , Met(O), Ser(Bzl), Ser(But),Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(But).

[0058] Amino protecting groups which are preferably used are thebenzyloxycarbonyl (Z) radical which can be eliminated by means ofcatalytic hydrogenation, the2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl (Ddz) radical or trityl(Trt) radical which can be eliminated by means of weak acids, and the9-fluorenylmethyloxycarbonyl (Fmoc) radical which can be eliminated bymeans of secondary amines.

[0059] In process variant A), a procedure is best followed in which thecompound of the formula II is reacted in an equimolar amount or in anexcess of up to three times in an inert solvent, such methanol, ethanolor isopropanol with a compound of the formula III (in thedihydrochloride form) with constant stirring to give a compound of theformula Ia or Ib. The reaction temperatures are 30 to 90° C., or 30° C.to the boiling point of the solvent, preferably 40 to 70° C., inparticular around 55° C.

[0060] The reaction times are from 15 minutes to 48 hours, preferablyfrom 30 minutes to 3 hours, particularly preferably from 1 to 2 hours.The end of the reaction can be determined for example by means of HPLC.

[0061] To isolate and purify the reaction products of the formula Ia orIb, the solvent may be distilled off, the dried reaction mixture may beneutralized in demineralized water with acids or bases, and zwitterionicproducts may be purified on an ion retardation column (for example thetype BIORAD® AG11A8) using demineralized water as the eluent. To purifycationic products, they are bound to a cation exchanger in the H⁺ formand eluted for example using a perchloric acid gradient.

[0062] The resulting compound of the formula Ia or Ib in which R² is—COOH is converted to the corresponding carboxylic ester (processvariant B) for example by dissolving 1 g of the hydrochloride of thecompound of the formula Ia or Ib in 20 ml of 0.2 NHCl in methanol,refluxing the mixture for 2 hours and subsequently evaporating it underreduced pressure. As is the case with nitrophenyl esters, theesterification reaction is accelerated by addition of equimolar amountsof dicyclohexylcarbodiimide as a water-binding agent.

[0063] The corresponding carboxamides of the formula Ia or Ib (processvariant C) can be obtained by dissolving 1 g of activated carboxylicester (for example of the p-nitrophenyl ester) of the compound of theformula Ia or Ib in 250 ml of dichloromethane and reacting the mixturewith gaseons NH₃ or with the corresponding amino acid or with a di- ortripeptide (with an addition of triethylamine). The reaction can bemonitored with the aid of the p-nitrophenolate which forms (developmentof a yellow color).

[0064] The starting compounds of the process variant A) are known or canbe obtained commercially.(S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid or(S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acidcan also be obtained microbiologically (Severin et al. J. Gen. Microb.(1992), 138, pages 1629-1638).

[0065] The cosmetic product is prepared by formulating at least onecompound of the formula Ia or Ib and/or one physiologically acceptablesalt of the compound of the formula Ia or Ib, if appropriate togetherwith auxiliaries and/or carrier substances, to give a suitableformulation. The auxiliaries and carrier substances belong to the groupof the carriers, preservatives and other customary auxiliaries.

[0066] The cosmetic products based on the compound of the formula Ia orIb are used externally.

[0067] Examples of use forms which may be mentioned are: solutions,suspensions, emulsions, pastes, ointments, gels, creams, lotions,powders, soaps, surfactant-containing cleansers, oils and sprays. Inaddition to the compound of the formula Ia or Ib, any desired customarycarrier substances, auxiliaries and, if appropriate, other activesubstances are added to the product.

[0068] Auxiliaries to be preferred belong to the group of thepreservatives, antioxidants, stabilizers, solubilizers, vitamins,colorants and odor improvers.

[0069] In addition to the compound of the formula Ia or Ib, ointments,pastes, creams and gels may comprise the customary carrier substances,for example animal and vegetable fats, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonites, silica, talc and zinc oxide or mixtures of these substances.

[0070] In addition to the compound of the formula Ia or Ib, powders andsprays may comprise the customary carrier substances, for examplelactose, talc, silica, aluminum hydroxide, calcium silicate andpolyamide powder, or mixtures of these substances. Sprays mayadditionally comprise the customary propellants, for examplechlorofluorohydrocarbons, propane/butane or dimethyl ether.

[0071] In addition to the compound of the formula Ia or Ib, solutionsand emulsions may comprise the customary carrier substances, such assolvents, solubilizers and emulsifiers, for example water, ethanol,isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylglycol, oils, in particularcottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil andsesame seed oil, glycerol fatty esters, polyethylene glycols and fattyacid esters of sorbitan or mixtures of these substances.

[0072] In addition to the compound of the formula Ia or Ib, suspensionsmay comprise the customary carrier substances, such as liquid diluents,for example water, ethanol or propylene glycol, suspending agents, forexample ethoxylated isostearyl alcohols, polyoxyethylene sorbitol estersand polyoxyethylene sorbitan esters, microcrystalline cellulose,aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixturesof these substances.

[0073] In addition to the compound of the formula Ia or Ib, soaps maycomprise the customary carrier substances, such as alkali metal salts offatty acids, salts of fatty acid hemiesters, fatty acid proteinhydrolyzates, isethionates, lanolin, fatty alcohol, vegetable oils,plant extracts, glycerol, sugars or mixtures of these substances.

[0074] In addition to the compound of the formula Ia or Ib,surfactant-containing cleansing products may comprise the customarycarrier substances, such as salts of fatty alcohol sulfates, fattyalcohol ether sulfates, sulfosuccinic monoesters, fatty acid proteinhydrolyzates, isethionates, imidazolinium derivatives, methyltaurates,sarcosinates, fatty acid amide ether sulfates, alkylamidobetaines, fattyalcohols, fatty acid glycerides, fatty acid diethanolamides, vegetableand synthetic oils, lanolin derivatives, ethoxylated glycerol fatty acidesters or mixtures of these substances.

[0075] In addition to the compound of the formula Ia or Ib, facial oilsand body oils may comprise the customary carrier substances, such assynthetic oils, such as fatty acid esters, fatty alcohols, siliconeoils, natural oils such as vegetable oils and oily plant extracts,paraffin oils, lanolin oils or mixtures of these substances.

[0076] Other characteristic use forms in cosmetology are lipsticks,lipsalve sticks, mascara, eyeliner, blusher, powder foundation, emulsionfoundation and wax foundation, and also suncare and after-sunpreparations.

[0077] The active concentration of the compound of the formula Ia or Ibin the cosmetic product according to the invention amounts to 0.1 to 10%by weight, preferably 0.1 to 3% by weight.

[0078] The invention furthermore relates to the use of the compound ofthe formula Ia or Ib for the preparation of cosmetic products for thecare and prophylaxis of dry and/or irritated skin and of dry flakyscalp, in particular for increasing and/or stabilizing the moisturecontent of the skin.

EXAMPLE 1 Preparation of(S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid

[0079] 60 ml of trimethyl orthoformate are dissolved in 400 ml ofmethanol, and reacted with 30 g of L-diaminobutyric acid×2 HCl at 55° C.with constant stirring. After a reaction time of 2 hours, the solvent isevaporated under reduced pressure, the crude product which remains isdissolved in 50 ml of demineralized water, and the solution isneutralized using NaOH. The compound is subsequently purified on an ionretardation column type BIORAD® AG11A8 (Bio-Rad Laboratories GmbH,Munich, Germany) using demineralized water as the eluent, and theproduct is dried and recrystallized from methanol. The compound obtainedcan be identified by means of high-pressure liquid chromatography(HPLC); (for example E. Merck, Darmstadt, Germany, LiChroCART® 125-NH₂5μ, eluent: 80% acetonitrile), and is characterized by the following¹³C-NMR data:

[0080] 176.8, 161.2, 53.8, 37.9, 22.0, 18.7 ppm (relative to TMS);(Galinski E. A., Pfeiffer H. P., Trüper H. G. (1985) Eur. J. Biochem.149, 135-139).

EXAMPLE 2 Cosmetic Activity

[0081] A) Water absorption capacity

[0082] The water absorption capacity of the compound of Example 1 isdetermined at a relative atmospheric humidity of 65%. The controlsubstances used are in each case glycerol and propylene glycol. In eachcase 1 g of the anhydrous substance is kept in a sealed chamber untilthe weight is constant. The water absorption capacity is calculated asfollows:${\text{Water absorption in \%} = {\frac{\quad {{{Weight}\quad {of}\quad {the}}\quad \quad {{amount}\quad {of}\quad {water}\quad {absorbed}}}\quad}{\quad {{{Weight}\quad {of}\quad {the}}{{dried}\quad {substance}}}} \times 100}}\quad$

[0083] Ectoin has a water absorption of 25% and, in comparison withglycerol or propylene glycol (60 and 45%, respectively) a lesspronounced hygroscopic behavior. However, with regard to its use as amoisturizer, the dehydrating effect known from unduly high glycerolconcentrations can be ruled out.

[0084] B) Hydration of the human skin

[0085] The hydration is measured capacitively using the Corneometer® CM820 (Courage & Khazaka Electronic GmbH). Here, the relatively highdielectric constant of water is exploited. The end face of the sensorcontains the measuring capacitor. When the measuring head is pressedagainst the skin, the horny layer reaches the scatter area of thecapacitor field. The changes in capacity differ as a function of thewater content. The short measuring time rules out errors caused bydeformation of the skin or evaporation build-up.

[0086] The forearm of 7 test subjects is treated once daily for 14 dayswith an emulsion comprising(S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid (compound ofExample 1, ectoin). As a control, the corresponding placebo emulsion isapplied to the other forearm. The data determined by the Corneometerdemonstrate that the hydration of human skin which has been treated withthe emulsion according to the invention is approximately 10% higher thanby direct comparison with the placebo emulsion. This means that thehydration of the human skin is markedly improved and significantlyhigher than the hydration achieved with the placebo emulsion.

[0087] The composition of the emulsions is shown in Table 1. TABLE 1Placebo emulsion A potassium cetyl phosphate 3.0% A glyceryl stearate4.0% A methoxy PEG-17/dodecyl glycol copolymer 1.0% A glyceryl laurate2.0% A ceteraryl alcohol 3.0% A steareth-21 0.3% A polymethylmethacrylate 1.0% A isocetyl alcohol 6.0% A macadamia nut oil 2.0% Adimethicone 2.0% A caprylic/capric triglyceride 4.0% Aperfluoropolymethyl isopropyl ether 0.5% A butylhydroxytoluene 0.02% Bpurified water 61.23% B sodium carbomer 0.25% B sorbeth-30 3.0% Bglycerol 2.0% B methyl gluceth-20 0.5% B ethylenediamine-N,N,N′,N′-tetraacetic 0.05% acid, tetrasodium salt B panthenol2.0% B preservative 1.9% B magnesium aluminum silicate 0.15% C perfume0.1% (S)-1,4,5,6-tetrahydro-2-methyl-4- pyrimidinecarboxylic acid(ectoin emulsion) A potassium cetyl phosphate 3.0% A glyceryl stearate4.0% A methoxy PEG-17/dodecyl glycol copolymer 1.0% A glyceryl laurate2.0% A ceteraryl alcohol 3.0% A steareth-21 0.3% A polymethylmethacrylate 1.0% A isocetyl alcohol 6.0% A macadamia nut oil 2.0% Adimethicone 2.0% A caprylic/capric triglyceride 4.0% Aperfluoropolymethyl isopropyl ether 0.5% A butylhydroxy toluene 0.02% Bpurified water 60.23% B sodium carbomer 0.25% B sorbeth-30 3.0% Bglycerol 2.0% B methyl gluceth-20 0.5% B ethylenediamine-N,N,N′,N′-tetracetic acid 0.05% tetrasodium salt B panthenol2.0% B preservative 1.9% B magnesium aluminum silicate 0.15% C perfume0.1% D (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimi- 1.0% dine carboxylicacid

1. A cosmetic composition containing an effective amount of at least onecompound of the formula Ia or Ib

and/or of a physiologically acceptable salt of the compound of theformula Ia or Ib and/or of a stereoisomeric form of the compound of theformula Ia or Ib for treatment of aged, dry or irritated skin or of dryflaky scalp; R¹ being defined as follows: a) a hydrogen atom or b)(C₁-C₄)-alkyl, R² being defined as follows: a) a hydrogen atom, b)—COOH, c)

d)

in which R⁵ is 1) a hydrogen atom, 2) (C₁-C₄)-alkyl, 3) an amino acidradical, 4) a dipeptide radical or 5) a tripeptide radical, R³ and R⁴independently of one another being defined as follows: a) a hydrogenatom or b) —OH, and n is the number 1, 2 or
 3. 2. The cosmeticcomposition as claimed in claim 1 , wherein the compound of the formulaIa or Ib is employed, R′ being defined as follows: a) a hydrogen atom orb) methyl, R² being defined as follows: a) a hydrogen atom or b) —COOH,R³ and R⁴ independently of one another being defined as follows: a) ahydrogen atom or b) —OH, and n is the number
 2. 3. The cosmeticcomposition as claimed in claim 1 , wherein(S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid and/or(S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidine carboxylic acidis employed.
 4. The cosmetic composition as claimed in claim 1 , whereinthe cosmetic product is employed in the form of a solution, asuspension, an emulsion, a paste, an ointment, a gel, a cream, a lotion,a powder, a soap, a surfactant-containing cleanser, an oil, a lipstick,a lipsalve stick, a mascara, an eyeliner, a blusher, a powderfoundation, an emulsion foundation or a wax foundation, a suncare andafter-sun preparation or a spray.
 5. A method of treating a patientsuffering from aged, dry or irritated skin or of dry, flaky scalp, whichcomprises administering an effective amount of the cosmetic compositionof claim 1 to said patient.
 6. A method of increasing or stabilizing themoisture content of a patient's skin, which comprises administering aneffective amount of the cosmetic composition of claim 1 to said patient.7. A compound of the tautomeric formula Ia or Ib

and/or of a physiologically acceptable salt of the compound of theformula Ia or Ib and/or of a stereoisomeric form of the compound of theformula Ia or Ib; R¹ being defined as follows: a) a hydrogen atom or b)(C₁-C₄)-alkyl, R² being defined as follows: a) a hydrogen atom, b)—COOH, c)

d)

in which R⁵ is 1) a hydrogen atom, 2) (C₁-C₄)-alkyl, 3) an amino acidradical, 4) a dipeptide radical or 5) a tripeptide radical, R³ and R⁴independently of one another being defined as follows: a) a hydrogenatom or b) —OH, and n is the number 1, 2 or 3, with the exception of thecompounds (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid or(S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidine carboxylicacid.
 8. A compound of the formula Ia or Ib as claimed in claim 7 ; R¹being defined as follows: a) a hydrogen atom or b) methyl, R² beingdefined as follows: a) a hydrogen atom or b) —COOH, R³ and R⁴independently of one another being defined as follows: a) a hydrogenatom or b) —OH, and n is the number
 2. 9. A process for the preparationof the compound of the formula Ia or Ib as claimed in claim 7 whichcomprise A) reacting a compound of the formula II

in which R¹ is as claimed in claim 1 , with a compound of the formulaIII

in the presence of an alcohol to give a compound of the formula Ia orIb, as claimed in claim 1 , R³, R⁴ and n being as defined in formula Iaas claimed in claim 1 and R² being a hydrogen atom or —COOH, or B)reacting a compound of the formula Ia or Ib as claimed in claim 1 inwhich R² is —COOH with an alkyl halide to give the correspondingcarboxylic esters of the compound of the formula Ia or Ib, or C)reacting a compound of the formula Ia or Ib as claimed in claim 1 , inwhich R² is an activated carboxylic ester with an amine of the formulaNH₂—R⁵ to give the corresponding carboxamide of the compound of theformula Ia or Ib.
 10. A process for the preparation of a cosmeticproduct, which comprises formulating at least one compound of theformula Ia or Ib as claimed in claim 1 and/or a physiological acceptablesalt of the compound of the formula Ia or Ib, if appropriate togetherwith auxiliaries and/or carrier substances, to give a suitable cosmeticformulation.